Diseases of The Exocrine Pancreas

Introduction:

The pancreas is a multifunctional glandular V-shaped organ located near the stomach and duodenum. The anatomical and functional juxtapositions of the duodenum, stomach, gall bladder (from the liver) and pancreas are shown below:

In addition to its digestive enzyme synthesis and secretion, the pancreas is also an endocrine gland, secreting hormones such as insulin and glucagon for the regulation of blood sugar (see Diabetes). The endocrine functionality of the pancreas will not be addressed on this page.

The most common problems related to the pancreas is pancreatitis (inflammation of the pancreas) and, to a much lesser extent, exocrine pancreatic insufficiency (EPI). Both of these topics will be addressed, though succinctly, on this page.

Pancreatitis-Dog:

Introduction:

Pancreatitis, by definition, means inflammation of the pancreas. The types of inflammation have been characterized as 1) edematous/interstitial, 2) hemorrhagic/necrotizing and 3) fibrotic; these represent significant differences in the severity of the disease, from mildest to end-stage (the replacement of inflamed, damaged pancreatic tissue with non-functional connective tissue). All forms of pancreatitis are potentially life-threatening as a result of primary disease and in many cases, the secondary metabolic derangements, including DIC (disseminated intravascular coagulopathy) and shock.

Causes:

Pancreatitis occurs in response to various insults; these include introduction of a single high-fat meal, hypercalcemia (elevated blood calcium levels), exposure to unusual (for the dog) foods, table scaps, getting into garbage, drugs (azathioprine, L-asparaginase, phenobarbital, bromide, sulfa-containing drugs, tetracycline [rare]), intoxicants (e.g. zinc, organophosphates), confounding medical conditions (e.g. Gastric-dilatation-volvulus, bile reflux disease, hyperlipidemia, pancreatic abcess, pancreatic neoplasia (with duct obstruction)). Stress, obesity and trauma are also risk factors and there are probably other environmental and physiologic factors we do not yet appreciate. Other risk factors include breed (small breeds more at risk than large breeds), previous gastrointestinal disease (non-specific), endocrine disease, such as diabetes mellitus , hyperadrenocorticism, hypothyroidism and surgery. Note: administration of exogenous corticosteroids, heretofor believed to predispose an animal to pancreatitis, is NOT a risk factor as once thought. The pathophysiology of each of these known inciting factors is complex and well beyond the scope of this treatise. It is enough to know that these risk factors and associations to pancreatitis exist.

Clinical Signs:

Signs of pancreatitis in dogs include the following: relatively acute onset of vomiting, diarrhea (possibly bloody), anorexia, abdominal pain, dehydration, and potentially one or more of the following complications: abdominal (fluid) distension, respiratory distress (thoracic fluid accumulation), fever, sepsis (systemic bacterial infection), cardiac arrhythmias and poor circulation/perfusion leading to shock. The appearance of these confounding clinical signs results from the ensuing onset of cardio-vascular collapse from DIC, sepsis, dehydration or all of these.

Diagnosis:

The diagnosis of pancreatitis in dogs is based in large part upon the results of clinical-pathology data, the physical exam and history, imaging techniques in some instances and if necessary, exploratory surgery with pancreatic biopsy and histopathologic assessment. Other causes of acute vomiting and diarrhea must be ruled out, including infectious and parasitical disease(s), metabolic disease(s) (e.g. liver-gall bladder, kidney, thyroid, adrenal, toxic, peritonitis), anatomical (e.g. foreign body obstruction, gastric dilatation-volvulus, gastrointestinal or splenic torsion, intussception or perforation), trauma.

Some clinical pathology abnormalities thought to be associated with pancreatitis in the dog are:

Elevation in canine serum amylase and/or lipase enzyme is NOT so useful, as previously thought:

Amylase has a specificity for pancreatitis of only 57.1% and a sensitivity of 62.1 %. This means that when amylase is elevated, it will be due to pancreatitis in only 57.1 cases out of 100 cases of elevated enzyme; also when pancreatitis is in fact present, it will only be elevated in 62.1 out of 100 cases. There are other causes of elevated amylase including renal insufficiency, non-specific upper gastrointestinal disease , hepatic disease, some neoplasms and as the result of treatment with certain drugs (e.g. "Hetastarch").

Lipase also has relatively low specificity with pancreatitis, (55.2%) though it is a little more sensitive (73.3%) than amylase. However, as with amylase, there are other conditions that can result in elevation of serum levels, including renal disease/failure, hepatic necrosis, various neoplasms (bile duct carcinoma, hepatocellular carcinoma, lymphosarcoma, cardiac hemagiosarcoma, intestinal adenocarcinoma or lymphoma,), amyloidosis, and paraquat intoxication

TLI (Trypsin-like immunoreactivity):

Once thought to be the definitive test for pancreatitis, this test also suffers from relatively low specificity (65.4%) and sensitivy (33.3%).

In one study only 40% of dogs with spontaneous (confirmed) pancreatitis had an elevated TLI

TLI has been seen to increase in situations where there is protein malnutrition in the absence of pancreatitis

TLI is more suitable for the diagnosis of exocrine pancreatitic insufficiency

c-PLI (canine pancreatic lipase):

Is the most pancreatitis-specific test, with specificity of ~78% and sensitivity between 82%-93%!

Pancreatic lipase is derived exclusively from the pancreas and thus abnormal elevations are usually the result of pancreatic pathology

Some animals without primary pancreatitis will also have elevated
c-PLI ; the pancreas can be an" innocent bystander" , incurring damage from inflammatory mediators generated by other processes, e.g. endotoxins, cytokines in the neighboring viscera and peritoneum.

Values of c-PLI less than 200 ug/L are negative for pancreatitis, whereas, values greater than 400 ug/L are likely pancreatitis. There is an "iffy" result (uncertain insterpretation) if the value for c-PLI lies between 200 ug/L - 400 ug/L

TLI is still considered more useful than c-PLI in the diagnosis of exocrine pancreatic insufficiency

Non-specific elevation of one or more liver enzymes (ALP, ALT, GGT)

Increased serum bilirubin

Hypocalcemia (decreased serum calcium)

Hypercholesterolemia (increased serum cholesterol)

Hyperglycemia (increased blood glucose)

Elevated blood urea nitrogen and/or creatinine:

Pre-renal (probably due to dehydration, gastrointestinal hemorrhage)

Or secondary effects on renal function from DIC or shock, where there is decreased blood-perfusion of the kidneys

Hypoalbuminemia (decreased serum albumin)

Non-specific electrolyte distrubances, usually secondary to dehydration from vomiting, diarrhea and decreased fluid and dietary intake

Diagnostic Imaging

On occasion, with ultrasound (or CT) it may be possible to ascertain architectural alterations of the normal pancreatic sonograph consistent with pancreatitis, especially in the hands of an experienced diagnostic imaging specialist

Vague, non-specific changes in the radiographic opacity of the right, cranial quadrant of the abdomen are sometimes related to the presence of pancreatic inflammation

Fine Needle Aspirate

An ultrasound-guided fine needle aspirate for cytological evaluation can be useful and the procedure is quite safe.

Exploratory Surgery

Can be useful for biopsying the pancreas and other portions of the gastrointestinal tract when the diagnosis is questionable, particulary if the animal is not responding to conventional therapy and other causes of these clinical signs have been ruled out

Treatment:

The treatment goals are to control pain and inflammation, correct fluid deficits and electrolyte imbalances while promoting perfusion (and healing) of the pancreas, gastrointestinal tract and kidneys, assess for and treat DIC ("disseminated intravascular coagulopathy") if present. The treatment of pancreatitis must be tailored to the severity of disease and the ever-changing status of the animal.

Mild Clinical Signs:

Intravenous fluids are administered at a rate determined to correct electrolyte disturbances and maintain hydration

Pain medication are provided, usually opioids such as butorphanol, buprenorphine, oxymorphone, meperidine, keeping in mind that these can inhibit normal gastrointestinal motility

If vomiting or nausea is present, then antiemetics (miropitant, odansetron, dolasetron, metoclopramide, butorphanol as a chronic infusion)

Animals are usually not offered food or water for 24-48 hours (or sometimes longer), to give the gastrointestinal tract and pancreas some time to heal; however feeding is encouraged if animal is not vomiting and not painful

The concurrent use of antibiotics is controversial in mild cases as bacterial infection is not usually a component of mild canine pancreatitis.

With improvement, water then low-fat, low-protein, easily digestible (simple carbohydrate) foods are offered for several days, until the animal is deemed "normal" at which time the normal diet is gradually reintroduced.

Moderate to Severe Clinical Signs

Animals are treated as described for Mild Clinical Signs, above, but additional considerations are added to the overall assessment and management regimen; sometimes colloidal fluids are needed, if hypoalbuminemia is severe

Analgesics: treating pain has been shown to markedly improve the prognosis in many cases. Also, given that pain can likewise trigger nausea and vomiting, addressing pain can beneficial to reduce the frequency of emesis. Non-steroidal antiinflammatory drugs (NSAIDs) should ALWAYS be avoided as these are potential gastrointestinal irritants.

Antiemetics: treating nausea and vomiting can significantly enhance the probability of recovery. The animal feels better, electrolyte imbalances and metabolic derangements are less likely, and the animal is more likely to respond to enteral feeding (see below). Miropitant, odansetron, dolasetron, metoclopramide, butorphanol as a chronic infusion are examples of helpful antiemetics

Assess for the presence of DIC (Coagulation profile, with FDPs [fibrinogen degradation products] or D-dimer, and AT-III (antithrobin-III) concentrations). If DIC is present, treatment is usually intravenous fresh-frozen plasma with heparin (dose depends on severity and stage) and periodic rechecks of the coagulation times and additional heparin subcutaneous injections.

Gastroprotectorants, such as antacids (famitodine, ranitidine or cimetadine) or sucralfate, direct acid-neutralizers or acid-inhibitors such as misoprostol or omeprazole, repectively

If hyperglycemia is severe, insulin therapy may be required. In fact, if pancreatitis is severe and the Islet cells (secreting insulin) are irreversibly damaged, the affected animal may become insulin-dependent (see Diabetes).

If possible, feeding through the normal gastrointestinal system (enteral feeding) is recommended if animal is not painful and not vomiting. Feeding helps intestinal mucosa heal and signifantly improves survival

Even if there is severe disease, if the animal has not eaten for 72-96 hours, enteral nutrition should be pursued, as feeding significantly improves probability of a timely recovery

The use of a nasoesophageal or nosogastric tube may be tried, using a liquid diet, such as Clinicare®; even if animal is occasionally vomiting, some of diet that is getting through is beneficial

Alternatively, an esophageal, stomach or jejunostomy tube can be surgically placed to allow feeding anorectic animals

Questionable treatments:

Intravenous fresh-frozen plasma was felt to be beneficial even in the absence of DIC
because it containe specific proteins and macroglobulins that inactivate pancreatic enzymes; however while fresh-frozen plasma may be useful to provide coagulation factors when these are depleted in DIC, there is no evidence that using it otherwise impacts the prognosis and ultimate outcome.

Dopamine as an infusion was thought to promote renal and pancreatic blood perfusion (hence hasten healing), though more recently the efficacy of including dopamine has been called into question

Vasopressin (or desmopressin): In humans, vasopressin has been used to treat septic, hypotensive, ("shocky") patients unresponsive to conventional therapy. It is not usually used in veterinary for this purpose, though its potential use for promoting perfusion of critical organs in dogs has been mentioned in the literature.

The use of corticosteroids in acute canine pancreatitis has not been shown to be of value in experimental studies.

Anitbiotics: infection is usually not involved in canine pancreatitis. However, in severe cases, where compromise of the intestinal mucosa integrity is suspected or if peritonitis is present, antibiotics should be considered

Pancreatitic enzyme replacement. While clearly useful in instances of exocrine pancreatic insufficiency, the usefulness of exogenous digestive enzymes to manage pancreatitis is controversial and not usually recommended

There may be a beneficial effect of selenium (0.3 mg/kg sodium selenite added to intravenous infusion solutions), presumably acting as an antioxidant. Unfortunately, the clinical studies were not properly controlled, and thus the usefulness of selenium is controversial.

Long-term Management
in cases of severe or recurring instances of canine pancreatitis

Monitor c-PLI initially every few weeks, then months, depending on the results of the physical exam and clinical signs, if any

Pancreatitis-Cat

Introduction:

Pancreatitis in the cat can present as acute onset of diarrhea, vomiting, inappetance or more commonly, as an insidious, recurring or chronic, intermittent diarrhea, vomiting or both. Either form can be mild or severe. There are several types of acute or chronic pancreatitis in the cat: necrotizing, hemorrhagic with multiple organ involvement, infiltrative (lymphocytic-plasmocytic type of inflammation). In some cats, a suppurative form, involving infectious organisms is seen. In cats with recurrence or persistance, there is often some degree of pancreatic fibosis (end-stage). Additionally, in many cats, there is concurrent inflammation of liver and upper gastrointestinal tissues, a syndrome euphemistically referred to as "triaditis". In the cat, the pancreatic duct, common bile duct and duodenum share the duodenal papilla (see above illustration); the co-involvement of upper intestinal, pancreatic and liver disease is, somehow, believed to be a result of that close association.

Pancreatitis is sometimes seen with diabetes mellitus, vitamin-K-responsive coagulopathy, hepatic (liver) cholangitis-cholangiohepatitis syndrome and what is descriptively termed "inflammatory bowel disease" (IBD). Approximately 38% of cats with Idiopathic Hepatic Lipidosis have concurrent pancreatitis.

Causes

Causes of pancreatitis in cats are less well appreciated, compared with dogs. About 90% are "idiopathic", meaning we do not know the underlying cause. However, some known associations predisposing to pancreatitis in the cat include: trauma or ischemia (tissue oxygen deprivation), exposure to organophosphates, infections (FIP, toxoplasmosis,herpes virus, feline distemper (parvo) virus, and liver fluke infestation), hypotension. Unlike the dog, pancreatitis in the cat is not associated with fat intake nor with the exposure to corticosteroids. In cats, pancreatitis can be focal (just specific area(s)) and also chronic-recurring. The latter is an insidious, smoldering form of the disease, an triggers of these episodes are unknown, Owners do not always realize that their cats are having an episode because clinical signs are non-specific. In cats, this form may in some instances be accompanied by hepatitis and/or upper intestinal inflammatory bowel disease (IBD). Remember that the pancreatic duct and common bile duct share a common duodenal papilla (i.e. they may communicate/affect delivery of the other fluid to the intestine). With chronic recurrence of inflammation, there is progressive loss of functional pancreatic tissue (replaced with scar tissue) and eventually some cats become diabetic and, sometimes develop exocrine pancreatic insufficiency (EPI)...where there is insufficient pancreatic proteolytic and lipolytic enzymes to digest complex protein and fat.

Clinical Signs

The clinical signs of acute pancreatitis in cats may include diarrhea and/or vomiting, lethargy, inappetance, abdominal pain, weakness, hyPOthermia (low body temperature) or hyPERthermia (elevated body temperature). Potential complications and resulting clinical signs in the acute form of the disease are similar to those described for the dog. If acute pancreatitis is severe, the prognosis is guarded. The chronic/recurring form of the disease is most often associated (in order of decreasing frequency) with lethargy, anorexia, dehydration, hypothermia, pain (difficult to discern in many cats), vomting, dyspnea (labored respiration), and lastly, diarrhea.

Diagnosis:

Diagnosis of pancreatitis in the cat is not easy.

Clinical Pathology

Elevations of bilirubin, and GGT, ALT, ALP can be seen and are confusing, because elevations of these is most commonly associated with liver disease (so...it is imperative to still consider pancreatitis on the list of diffential diagnoses)

Hypocalcemia

Is seen in about 64% of cats with pancreatitis

If total calcium is low, one should check the ionized calcium level (iCa++ ), which is low in about 61% of cats; values of iCa++ less than 1mmol/L are associated with a very poor prognosis

Serum Amylase/Lipase enzymes

Neither amylase nor lipase levels correlate with pancreatitis in the cat. These enzymes are of no use for diagnosing pancreatitis in the cat (and of arguable use for diagnosing pancreatitis in the dog as well)

TLI (trypsin-like immunoreactivity) may or may not be elevated, similar to the dog; positive changes are most likely to be seen only in cases of severe pancreatitis and then only within the first few hours following the onset of an episode; however, with chronicity, there is progressive destruction of pancreatic tissue and fibrosis. In some animals, the pancreas is barely functional and these animals now exhibit signs of exocrine pancreatic insufficiency (EPI). A low value for the TLI test can help make the diagnosis of EPI.

f-PLI, feline pancreatic lipase, is specific and the most reliable non-invasive test for the presence of pancreatitis in the cat.
Unfortunately, in cats with the chronic recurring form of pancreatitis, f-PLI is elevated in only 65% of animals, in large part probably because there is progressively less viable pancreatic tissue than in a healthy animal

Diagnostic imaging.

Vague changes in the radiological appearance of the right or left cranial abdominal quadrant may be noticed; these are not specific

In cats, pancreatitis is often a focal disease, so radiographic appearance may not meet the criteria for diagnosis established in dogs

CT or ultrasonographic appearance of the pancreas can be diagnostic in the hands of an experienced diagnostic imaging specialist if there is diffuse, active disease. With focal inflammation, the ultrasound may not see significant, abnormalities.

Exploratory Surgery

Exploratory surgery with biopsy of the pancreas is sometimes required to definitively diagnose pancreatitis, especially if the animal is non-responsive and other etiologies for the clinical signs must also be considered (via biopsy)

Treatment

Treatment of feline pancreatitis is similar to that of the dog. However, it is acceptable and useful to give small doses of corticosteroids in some cases of feline pancreatitis (not complicated by diabetes mellitus), in order to quel the intensity of the inflammatory process. Unlike the dog, corticosteroid exposure in cats is not considered a risk factor for the initiation or exacerbation of ongoing pancreatitis. Additionally, in cats it is important to initiate feeding relatively early in the course of the disease, compared to dogs, even in the face of persistent clinical signs. Prolonged anorexia is associated with increased mortality from complications of hepatic lipidosis. Various techniques for feeding anorexic and even vomiting cats are described in the literature including "trickle feeding", syringe feeding, placement of stomach tubes, nasogastric tubes, esophageal tubes, j-tubes, etc, TPN (total parenteral nutrition), PPN (partial parenteral nutrition). These will not be discussed here.

Goals of therapy for acute disease is supportive:

Control pain: this is extremely important

Control vomiting and nausea if present (with antiemetics): this is important because nutritional support, preferably via enteral (gastrointestinal) route is necessary;

"Appropriate" enteral diet(s) may be similar to that described, below, for chronic pancreatitis

Goal of therapy for chronic recurring disease

Same as for acute, plus possible long-term dietary therapy; though at present, ideal diets are not yet known

Since many cats have concurrent disease (IBD, liver), diets that are friendly, highly digestible, and if indicated by history, hypoallergenic

Highly digestible usually implies moderately low fat (even though fat is not considered a contributory factor to episodes of pancreatitis in cats)

Cats have evolved to require some fat in the diet...so one must consider that when offering dietary modification; don't offer ultra-low fat diets

There are some that suggest that novel antigen diets may be beneficial in cats with pancreatitis because of the presumed relationship of feline pancreatitis with intestinal inflammation (IBD) (dietary allergy??)

Hydrolyzed (predigested) diets?

These are not necessarily low in fat, so may not be truly highly digestible

Exocrine Pancreatic Insufficiency

Introduction:

Exocrine Pancreatic Insufficiency (EPI) refers to the inadequate production (in the pancreatic acinar cells) and release (via pancreatic duct system) of exocrine pancreatic digestive enzymes. Pancreatic acinar atrophy is the most common cause of EPI in the dog; chronic recurring pancreatitis with resulting scarring of pancreatic tissue is the most common cause in the cat. In some instances of chronic pancreatitis in cats, concurrent diabetes mellitus occurs, due to simultaneous destruction of Islet cells (which synthesize insulin). Other causes of EPI include pancreatic neoplasia, and, rarely, congenital aplasia or hypoplasia of pancreatic acinar cells. Additionally, in German Shepherds and Border Collies a form of immune-mediated pancreatitis, usually subclinical, has been identified that leads to irreversible loss of pancreatic acinar function. Interestingly, the exocrine acinar system normally has a great functional reserve (about 10 fold greater functional ability than is physiologically required for normal digestive needs); this means that greater than 90% of the exocrine pancreas' functionality must be lost before clinical signs are manifest.

In the presence of EPI, the intestine lacks trophic factors...substances required to maintain integrity and absorptive capability. Thus, animals suffer in two ways: 1) inability to digest many foodstuffs due to lack of pancreatic digestive enzymes, and 2) inability to absorb predigested or partially digested nutrients. Nutrients remain in the intestine to feed bacteria, leading to diarrhea and steatorrhea. Malassimilation of nutrients leads to weight loss...sometimes emaciation...with accompanying vitamin deficiencies.

Clinical Signs:

Most affected animals present with polyphagia, severe weight loss and diarrhea. In cats, affected animals may also be seen to vomit and, on occasion, be inappetant. Feces are generally pale, loose, voluminous, greasy and markedly maloderous (due to steatorrhea).

Diagnosis:

Routine bloodwork is generally not diagnostic; diagnostic imaging is also not particularly useful for diagnosing EPI. Fecal proteolytic active (FPA) can be used; however, samples of frozen feces must be obtained on 3 consecutive days and evaluated for the presence or absence (as with EPI) of proteolytic enzyme activity. If samples are not handled correctly, false positive results (absence of proteolytic activity) suggesting EPI may be obtained.

TLI (trypsin-like immunoreactivity) has suggested as a reliable, specific and sensitive test for EPI in dogs and cats (ACVIM Proceedings 2002, Williams & Steiner). A commercially available elisa test for canine TLI (c-TLI) is available from Diagnostic Products Corporation, 5700 West 96th Street, Los Angeles, CA 90045. Dogs with small intestinal disease other than EPI have normal levels of trypsin-like immunoreactivity whereas, dogs with EPI have little or no detectable activity. According to the paper, this simple test will be positive in cases of EPI even before dramatic clinical signs are apparent. A feline specific TLI (f-TLI) has also been developed and is available at Texas A&M Gastrointestinal Function Test Laboratory. Both canine and feline TLI tests are performed on blood samples obtained from fasted animals. These samples are stable and can be shipped to the testing laboratory via conventional methods.

Treatment:

Usually, supplementing the diet with commercially available pancreatic enzymes is all that is required. Enzymes are mixed with food; preincubation prior to feeding is usually not necessary or beneficial. The enzyme preparations are somewhat expensive and substitution with chopped, raw pancreases of pig, ox or similar species may be economically more acceptable.

One problem faced by a number of patients is that exogenously suppied pancreatic-derived lipase enzymes (which digest fat) may be inactivated when contacted with stomach acid/juices. Preincubation of food with enzymes required for digestion does not improve fat digestion, probably because the optimal conditions for lipase activity occur within the environment of the proximal small intestine, where bile and bile acids, warm temperature and appropriate pH are present. No improvements in lipase activity is seen when gastric acid inhibitors or neutralizers (antacids) were included in the diets of some affected EPI patients. It may be possible to formulate pancreatic enzyme preparations as extended or sustained release preparations, permitting some of the enzyme to reach the small intestine where more optimal conditions exist for fat digestion to occur. No such preparation is yet available, however. Additionally, evidence suggests that high-fiber in the diet may further inhibit pancreatic enzyme activity, suggesting that dietary fiber should be minimal.

Current recommendations are therefore to feed a highly digestible low fiber diet, low in fats. In some instances supplementation with medium chain triglycerides may be beneficial. It has been thought that these can be hydrolyzed by naturally occuring gastic (stomach) lipases and/or can be absorbed intact without the action of pancreatic lipase. There is, however, evidence that even medium-chain triglycerides may require at least some pancreatic lipase activity; therefore, some patients with EPI still might not tolerate this form of dietary supplement.

Vitamin supplementation is also recommended, at least for the intial few weeks (except B12) after diagnosis, as most animals are deficient in B12, vitamins D, E, A and K. In animals in which small intestinal bacterial overgrowth remains a component of continued diarrhea, a short course of appropriate antibiotics may also be warranted. Even in animals supplemented with pancreatic enzymes, injectable vitamin B12 is required for the long term, because the absorption of oral B12 is dependent on species-specific "intrinsic factor" from the pancreas, which is non-functional in these animals.